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• W2162218084 endingPage "G695" @default.
• W2162218084 startingPage "G685" @default.
• W2162218084 abstract "Sterol 12α-hydroxylase (CYP8B1) catalyzes cholic acid synthesis in the liver and is feedback inhibited by bile acids. In addition to activating farnesoid X receptor (nuclear receptor subfamily 1H4), bile acids also induce inflammatory cytokines in hepatocytes. The objective of this study was to investigate the mechanism by which inflammatory cytokines inhibit human CYP8B1 gene transcription. Real-time PCR assays revealed that both chenodeoxycholic acid (CDCA) and interleukin-1β (IL-1β) markedly reduced CYP8B1, cholesterol 7α-hydroxylase CYP7A1 and hepatic nuclear factor 4α (HNF4α) mRNA expression levels in human primary hepatocytes. However, CDCA induced, but IL-1β reduced, small heterodimer partner (SHP) mRNA expression. IL-1β inhibited human CYP8B1 reporter activity only in liver cells, and a c-Jun NH 2 -terminal kinase (JNK)-specific inhibitor-blocked IL-1β inhibition. Activated JNK1 or c-Jun inhibited, whereas their dominant negative forms blocked, IL-1β inhibition of CYP8B1 transcription. Mutagenesis analyses mapped an IL-1β response element to a previously identified bile acid response element, which contains an HNF4α binding site. A dominant negative HNF4α inhibited CYP8B1 gene transcription and ectopically expressed HNF4α blocked IL-1β inhibition. Furthermore, IL-1β inhibited HNF4α gene transcription, protein expression, and binding to the CYP8B1 gene. JNK1 phosphorylated HNF4α and a JNK-specific inhibitor blocked the IL-1β inhibition of HNF4α expression. These results suggest that IL-1β inhibits CYP8B1 gene transcription via a mitogen-activated protein kinase/JNK pathway that inhibits HNF4α gene expression and its DNA-binding ability. This mechanism may play an important role in the adaptive response to inflammatory cytokines and in the protection of the liver during cholestasis." @default.
• W2162218084 created "2016-06-24" @default.
• W2162218084 creator A5002732282 @default.
• W2162218084 creator A5029861684 @default.
• W2162218084 date "2005-04-01" @default.
• W2162218084 modified "2023-09-25" @default.
• W2162218084 title "Cytokine regulation of human sterol 12α-hydroxylase (<i>CYP8B1</i>) gene" @default.
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• W2162218084 doi "https://doi.org/10.1152/ajpgi.00207.2004" @default.
• W2162218084 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/15550563" @default.
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